tbuckley/cabot-search huggingface dataset:
A DEIRGs-based immune score model for predicting prognosis and immunotherapy effects in breast cancer.
Authors: Fei Qu, Wei Li, Yongmei Yin
Journal: Journal of Clinical Oncology (2022)

e13558 Background: Immune-based strategies have reignited prospect for the treatment of breast cancer(BRCA).Nevertheless, due to the molecular and genetic heterogeneity of tumors, a single biomarker can no longer meet the clinical needs in the highly complex tumor microenvironment(TMB).The main purpose of this study was to explore the immunobiological markers of BRCA prognosis in help to guide patient management and establish personalized risk assessment. Methods: Univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis was used to establish a DEIRGs-based model in BRCA.GSEA analysis was used to explore biological signaling pathways. The immune infiltration landscape of BRCA was conducted via CIBERSORT algorithms and immunotherapy response was calculated through TIDE algorithm and TMB analysis. Results: In this study, 1178 BRCA samples from The Cancer Genome Atlas (TCGA) were used as the training set, and 140 samples from Gene Expression Omnibus (GEO) database were used as the validation set. Immune-related genes were collected from ImmPort and Innatedb database. A total of 547 differentially expressed immune related genes(DEIRGs) were identified. Enrichment analysis of the DEIRGs revealed that they were involved in the regulation of the P13K-Akt signaling pathway and cytokine–cytokine receptor interaction. To identify the genes most relevant to BRCA, we performed a WGCNA analysis to select the modules with the strongest correlation between the module traits. A signature based on six DEIRGs(CETP, DES, IL33, TXNIP, RNF125, STAT5B) was constructed. These cases were stratified into high- and low-risk groups according to the median risk score. Kaplan–Meier analysis showed that OS in the high-risk group was significantly shorter than that in the low-risk group (P&lt;0.001).The model presented unique characteristics in terms of immune cell infiltration and immune function in TME. The results from the tumor mutation burden(TMB) and tumor immune dysfunction and exclusion(TIDE) analysis revealed that the model could efficiently predict the potential response of immunotherapy. ROC curves were primarily used to assess the predictive power of the prognostic model, with AUC values of 0.736, 0.816 and 0.836 at 10, 15 and 20 years, respectively. More importantly, we researched the relationship between this model and TMB and TIDE score, which confirmed that this signature gave the best prognostic value. Conclusions: We have developed a novel immune score model, which can effectively and efficiently predict the prognosis of BRCA patients as well as the effect of immunotherapy. The high-risk subtype was featured by higher TIDE score and lower TMB. Our findings suggest that immunotherapy may be efficacious for low-risk groups of BRCA patients. The findings can be served as reference for the further research and validation of biomarkers.
Effect of Reflectance Confocal Microscopy for Suspect Lesions on Diagnostic Accuracy in Melanoma
Authors: Giovanni Pellacani, Francesca Farnetani, Silvana Ciardo, Johanna Chester, Shaniko Kaleci, Laura Mazzoni, Sara Bassoli, Alice Casari, Riccardo Pampena, Marica Mirra, Michela Lai, Serena Magi, Victor D. Mandel, Sergio Di Matteo, Giorgio Lorenzo Colombo, Ignazio Stanganelli, Caterina Longo
Journal: JAMA Dermatology (2022)

Previous systematic reviews and meta-analyses have concluded that given data paucity, a comparison of reflectance confocal microscopy (RCM) with dermoscopy is complex. They recommend comparative prospective studies in a real-world setting of suspect lesions.To test the hypothesis that RCM reduces unnecessary lesion excision by more than 30% and identifies all melanoma lesions thicker than 0.5 mm at baseline.This randomized clinical trial included 3165 patients enrolled from 3 dermatology referral centers in Italy between January 2017 and December 2019, with a mean (SD) follow-up of 9.6 (6.9) months (range, 1.9-37.0 months). The consecutive sample of 3165 suspect lesions determined through dermoscopy were eligible for inclusion (10 patients refused). Diagnostic analysis included 3078 patients (48 lost, 39 refused excision). Data were analyzed between April and September 2021.Patients were randomly assigned 1:1 to standard therapeutic care (clinical and dermoscopy evaluation) with or without adjunctive RCM. Information available guided prospective clinical decision-making (excision or follow-up).Hypotheses were defined prior to study initiation. All lesions excised (baseline and follow-up) were registered, including histopathological diagnoses/no change at dermoscopy follow-up (with or without adjunctive RCM). Number needed to excise (total number of excised lesions/number of melanomas) and Breslow thickness of delayed diagnosed melanomas were calculated based on real-life, prospective, clinical decision-making.Among the 3165 participants, 1608 (50.8%) were male, and mean (SD) age was 49.3 (14.9) years. When compared with standard therapeutic care only, adjunctive RCM was associated with a higher positive predictive value (18.9 vs 33.3), lower benign to malignant ratio (3.7:1.0 vs 1.8:1.0), and a number needed to excise reduction of 43.4% (5.3 vs 3.0). All lesions (n = 15) with delayed melanoma diagnoses were thinner than 0.5 mm.This randomized clinical trial shows that adjunctive use of RCM for suspect lesions reduces unnecessary excisions and assures the removal of aggressive melanomas at baseline in a real-life, clinical decision-making application for referral centers with RCM.ClinicalTrials.gov Identifier: NCT04789421.
Pan-cancer analysis of IDH1 and IDH2 genomic alterations to reveal a complex molecular landscape.
Authors: Houjun Zhou, Zhe He
Journal: Journal of Clinical Oncology (2022)

e15116 Background: As a crucial enzyme involved in cell aerobic metabolism of the tricarboxylic acid cycle, IDH also plays important role in cancer biology. Somatic point mutations in IDH1/2 contribute to oncogenesis by promoting the production and secretion of an oncometabolite, the D-2-hydroxybutyrate, which could alter cellular metabolism and epigenetic regulation. However, data regarding the status and prevalence of IDH1 and IDH2 mutations in pan-cancer from Chinese cancer patients is limited. Methods: Ranging from Jan 14, 2020, to Oct 25, 2021, genomic DNA extracted from 5419 blood or tissue samples involving more than 22 solid tumors types were analyzed by NGS assay to investigate the landscape of IDH1/2 mutations and hotspots. Results: IDH mutations were identified in 205 cases (3.78%), of which 145 cases (2.68%) were from the IDH1 mutations group and 63 cases (1.16%) from the IDH2 mutations group. IDH1 mutations predominantly occurred in CNS tumors, melanoma, and endometrial cancer (with mutation frequencies of 26.09%, 7.41%, 5.26%, respectively), whereas IDH2 mutations occurred commonly in endometrial cancer (5.26%) and gastric cancer (2.90%). Among the 56 mutation sites found in IDH1, Y208(19.46%), R132(16.11%), and R20(12.08%) were the three major IDH1 mutations. M397, which accounts for 33.33% of all IDH2 mutation sites, was the most significantly mutated subtypes, followed by T146(4.76%). Conclusions: Compared with IDH2, IDH1 is more frequently mutated in terms of cancer species as well as shows higher mutation frequency, and our findings implicate mutations in IDH in the pathogenesis of cancers, especially CNS tumors.
Change in atherogenic lipids during prostate cancer treatment with Gonadotropin Releasing Hormones agonists (GnRH) in men with type 2 diabetes mellitus: A nationwide, population-based cohort study
Authors: E. Lin, H. Garmo, E. Hagström, M. Van Hemelrijck, J. Adolfsson, P. Stattin, B. Zethelius, D. Crawley
Journal: European Urology (2022)
Comprehensive genomic profiling (CGP) of chromophobe renal cell carcinoma (chrRCC) compared with non-chromophobe RCC (nonchrRCC): Impact of <i>FLCN</i> genomic alteration (GA) status.
Authors: Gennady Bratslavsky, Andrea Necchi, Petros Grivas, Joseph M Jacob, Oleksandr Kravtsov, Richard S.P. Huang, Natalie Danziger, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2022)

4550 Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with nonchrRCC. Methods: 109 chrRCC and 5,862 nonchrRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female (37 [34%] vs. 1,817 [31%]) and younger than pts with nonchrRCC (median age 58 vs 62 years, p &lt;.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in the nonchrRCC cases only at 2.3% with 37% of the GA being germline. 1/109 (0.9%) of chrRCC featured a germline FLCN GA. GA/tumor were slightly higher in nonchrRCC vs chrRCC (3.6 vs 2.4; NS). There were no significant differences in gLOH, genomic signatures or ancestry between the groups. GA more frequent in chrRCC included TP53, RB1, PTEN. GA more frequent in the nonchrRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Biomarkers of immune checkpoint inhibitor (ICPI) drug response revealed higher mean TMB, TMB ≥10 mutations/Mb and PBRM1 inactivating mutation frequencies in the nonchrRCC than the chrRCC indicating possible differences in IO drug response. Conclusions: FLCN mutations that are associated with familial incidence of chrRCC are rarely associated with sporadic chrRCC. Sporadic chrRCC has a substantially different genomic profile from nonchrRCC and appears to harbor fewer opportunities for both targeted and immunotherapies. [Table: see text]
The influence of carrying BRCA pathogenic mutations in ovarian cancer and its platinum-sensitivity: 5-year experience of a tertiary center.
Authors: Pablo Jiménez Labaig, Lara Lombardero, Maria Pilar Rivero, Failah Mohamed Lamin, Berezi Ortega, Nagore Miñambres, Natalia Fuente, Ines Marrodan, Estibaliz Iza, Sergio Carrera, Eluska Iruarrizaga, Aintzane Sancho, Itziar Rubio, Joan Manel Mañe
Journal: Journal of Clinical Oncology (2022)

e17572 Background: Platinum-based chemotherapy still remains as the backbone treatment in ovarian cancer (OC) and its homologous tumors (primary peritoneal PP and fallopian tube FT cancer). BRCA mutational status is a sensitivity predictor to platinum chemotherapy. The aim of this study is to quantify the benefit of carrying a BRCA mutation along the subsequent platinum treatments and beyond. Methods: A descriptive, retrospective, single center study was developed in a tertiary hospital. OC, PP and FT neoplasms in stage III/IV, treated between 01/2015 and 12/2020 were included. Demographic characteristics, BRCA and HRD pathogenic mutational status, platinum-sensitive survival (PSS), platinum-resistant survival (PRS) and overall survival were analyzed. A p-value of &lt; 0.05 was considered statistically significant. Results: 116 patients were recruited (96 OC, 9 PP, 7 FT). 100 were non-BRCA mutated (including 2 germline BRIP, 1 RAD51C), 16 were BRCA-mutated (8 germline BRCA1, 7 germline BRCA2, 1 somatic BRCA2). 83 (71.6%) were stage III at diagnosis and 33 (28.4%) stage IV. Histologically, 90 cases were serous subtype (77.6%), 40.5% were grade 3. Mean age was 62.1 years. 90 (77.6%) received oncological surgery (debulking or interval procedure). A table is annexed with demographic characteristics without unbalanced distribution.Between BRCA-mutated group and non-mutated, the mean of platinum-based treatments was 2.63 (range 1-7) vs 2.49 (1-8), median PSS 42,8 months (9.7-80.1) vs 24.5 (2-78.9) HR 0.27 (95% IC 0.07-0.88. Log rank p-value 0.019), median PRS 20.3 (16-24.9) vs 9 (1.3-67.4) HR 1.1 p-value 0.715, and overall survival of 43.4 (11.3-81.4) vs 29 (0.7-78.9) HR 0.8 p-value 0.083. In contrast, histology factors, tumor markers, type of performed surgery, maintenance treatments and nonplatinum treatments didn’t result in a significant benefit as being carrier of BRCA mutation showed. Conclusions: Our analysis confirms that the platinum sensitive survival is deeply depend on the BRCA mutational status, remaining the most beneficial prognostic and predictive factor in the operated III/IV stages.[Table: see text]
Development and validation of an individualized immune prognostic signature in colorectal cancer.
Authors: Yang Liu, Liwen Zhang, Dong You
Journal: Journal of Clinical Oncology (2022)

e15531 Background: Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide with more than 1.85 million cases and 850,000 deaths annually. Although the outcome of CRC patients has improved significantly with the recent implementation of annual screening programs, reliable prognostic biomarkers are still needed due to the disease heterogeneity. Accumulating evidence revealed an association between immune signature and CRC prognosis. Therefore, we aim to build a robust immune-related gene pairs (IRGPs) signature that can evaluate the prognosis for CRC patients. Methods: Gene expression profiles and complete clinical information of CRC patients were collected from seven public cohorts, divided into the training cohort (TCGA cohort, N = 460) and six independent validation cohorts (GSE17536, GSE39582, GSE30378, GSE41258, GSE71187 and GSE87211, N = 1,151). Gene expression level in a specific sample or profile underwent pairwise comparison to generate a score for each IRGP. An IRGP score of 1 was assigned if IRG 1 was less than IRG 2; otherwise, the IRGP score was 0. Prognostic IRGPs were selected using log-rank test and LASSO Cox proportional hazards regression model. Kaplan-Meier curves and receiver operating characteristic (ROC) curves were used to examine model predictive performance in the validation cohort. Results: Within 942 immune-related genes that were expressed in all the cohorts, a prognostic immune signature of 80 gene pairs consisting of 101 unique genes was constructed which was significantly associated with patients overall survival in the training dataset (HR, 4.53 [2.89-7.09]; P &lt; 0.0001). In the validation cohorts, the IRGPs signature significantly stratified patients into high-risk and low-risk groups in terms of prognosis and was prognostic in multivariate analyses (HR, 3.08 [2.03-4.65]; P &lt; 0.0001). Biological processes that were dramatically involved in cancer immunology, such as cell chemotaxis and leukocyte migration, were enriched among genes in the IRGPs signature. To further improve accuracy, we combined tumor stage and IRGPs score to fit a Cox proportional hazards regression model using the training dataset and derived an immune-clinical prognostic index (ICPI) as (0.53633 × stage) + (1.31369 × IRGPs score). Significantly improved estimation of survival was achieved by ICPI relative to IRGPs score (mean C-index, 0.81 vs 0.79; P = 0 .014). Conclusions: We developed a robust IRGPs signature for estimating prognosis in CRC patients, providing new insights into the identification of CRC patients with a high risk of mortality. Prospective studies are needed to further validate its analytical accuracy and to test its clinical utility in individualized management of CRC patients.
Predicting patient treatment response and resistance via single-cell transcriptomics of their tumors.
Authors: Sanju SInha, Rahulsimham Vegesna, Saugato Rahman Dhruba, Wei Wu, D. Lucas Kerr, Oleg V. Stroganov, Ivan Grishagin, Kenneth D. Aldape, Collin M. Blakely, Peng Jiang, Craig J Thomas, Trever G. Bivona, Alejandro Schaffer, Eytan Ruppin
Journal: Journal of Clinical Oncology (2022)

e20540 Background: Tailoring the best treatments to cancer patients is an important open challenge. Here, we build a precision oncology data science and software framework for PERsonalized single-Cell Expression-based Planning for Treatments In Oncology (PERCEPTION). Methods: Our approach capitalizes on recently published matched bulk and single-cell transcriptome profiles of large-scale cell-line drug screens to build treatment response models from patients’ single-cell (SC) tumor transcriptomics. Our approach is a two-step process: first, the prediction models are trained on large-scale bulk-expression profiles of cancer cell lines and then, in a second step, the models’ performance is further optimized by training on SC-expression profiles of cancer cell lines. Results: First, we show that PERCEPTION successfully predicts the response to monotherapy and combination treatments in screens performed in cancer and patient-tumor-derived primary cells based on SC-expression profiles. Second, it successfully stratifies responders to combination therapy based on the patients’ tumor’s SC-expression in two very recent multiple myeloma and breast cancer clinical trials. Thirdly, it captures the development of clinical resistance to five standard tyrosine kinase inhibitors using tumor SC-expression profiles obtained during treatment in a lung cancer patients’ cohort. Notably, PERCEPTION outperforms state-of-the-art bulk expression-based predictors in all three clinical cohorts. Conclusions: In sum, this study provides a first-of-its-kind conceptual and computational method that is predictive of response to therapy in patients, based on the clonal SC gene expression of their tumors.
LGG-35. Dyslipidemia in children treated with BRAF inhibitors for brain tumor, a new side effect? A single center retrospective study
Authors: Marco Crocco, Antonio Verrico, Claudia Milanaccio, Gianluca Piccolo, Gabriele Gaggero, Patrizia De Marco, Valentina Iurilli, Sonia Di Profio, Maria Grazia Calevo, Emilio Casalini, Natascia Di Iorgi
Journal: Neuro-Oncology (2022)

Abstract The targeted therapies for brain tumors are innovative and promising oncological treatments and as a result their use has expanded widely. BRAF inhibitors (BRAFi) in recent years have played a central role in disease control of unresectable BRAF-mutated pediatric low-grade gliomas (LGG). Understanding the side effects of these drugs is crucial for clinical practice. The aim of the study was to investigate retrospectively the acute and long-term effects of vemurafenib on lipid metabolism in children treated for an LGG. Children (n=6) treated with vemurafenib at the mean age of 8.41±6.1 exhibited early alterations in plasma lipid profile as demonstrated after 1 month (n=4) by high plasma levels of Low-Density Lipoprotein (LDL 139.5±51.5,mg/dL), Total Cholesterol (TC 221.5±42.1,mg/dL) and Triglycerides (TG 107.8±44.4,mg/dL). Despite dietary recommendations, dyslipidemia persisted 3 months later (LDL 148.8±40.2,mg/dL; TC 238±36.5,mg/dL; TG 115±45.6,mg/dL; n=4) and at long distance follow-up (38±23,months) after treatment with vemurafenib: LDL 139.2±49.1,mg/dL; TC 216.5±38.4,mg/dL; TG 129.7±83.4 mg/dL. This potential side effect suddenly resolved itself in the only patient in which a change of therapy was made (to the combination of dabrafenib and trametinib). BMI was compatible with overweight/obesity at baseline (mean BMI-SDS 0.9±1.8) in 2 patient and normal in 4 patients: during follow-up BMI remained stable in 5 patients and increased in 1 patient. Our findings highlight that Vemurafenib could be associated with an increased risk of dyslipidemia independently of weight. This risk should be anticipated by the identification of high-risk patients and managed by close monitoring of metabolic parameters during routinely follow-up. The association of dabrafenib with trametinib seem not be associated to dyslipidemia, yet more data are needed to explore the hypothesis about the possible role to reduce the risk of dyslipidemia.
MEDB-26. Outcomes of children with standard-risk and high-risk medulloblastoma treated with pre-irradiation chemotherapy and risk-adapted craniospinal irradiation: a report on patients from the Polish Pediatric Neuro-oncology Group
Authors: Marta Perek-Polnik, Anne Cochrane, M Chojnacka, M Drogosiewicz, I Filipek, E Swieszkowska, M Tarasinska, P Kowalczyk, Mohamed S Abdelbaki, Bożenna Dembowska-Bagińska
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The last two decades have witnessed several efforts to minimize the adverse sequelae of craniospinal irradiation (CSI), a standard of care treatment modality in medulloblastoma. This has been accomplished by adding chemotherapy to the treatment backbone. The use of pre-irradiation chemotherapy has also been previously reported. In one of the largest studies to date, we analyze treatment outcomes in children with standard and high-risk medulloblastoma treated with pre-irradiation chemotherapy followed by reduced-dose radiotherapy in SR and maintenance chemotherapy. METHODS: Data from the Polish Pediatric Neuro-oncology Group (PPNG) was analyzed in patients greater than 3 years of age with newly-diagnosed medulloblastoma. RESULTS : Among 138 patients, median age at diagnosis was 7.9 years and median follow-up was 5.5 years. Comprehensive molecular subgrouping was not available for all patients at the time of data collection. Of 60 standard-risk patients, there was pre-irradiation disease recurrence in one patient. One patient expired prior to radiation due to metastatic disease. Of 78 high-risk patients, one had pre-irradiation recurrence. Overall survival (OS) for high-risk patients at 3 and 5 years (± standard error) was 89.2 ± 4.0% and 81.3 ± 5.8%, respectively. OS for standard-risk patients at 3 and 5 years was 92.5 ± 3.8% and 88.2 ± 5.1%, respectively. Among high-risk patients, event-free survival (EFS) at 3 and 5 years was 82.5 ± 5.3% and 81.0 ± 5.6%. Among standard-risk patients, 3-year EFS was 89.2 ± 4.6% and 5-year EFS was 86.8 ± 5.3%. CONCLUSION : This study demonstrates promising survival outcomes in pediatric medulloblastoma patients treated with pre-irradiation chemotherapy followed by reduced-dose CSI and adjuvant chemotherapy. Such an approach may be helpful if delays in starting radiotherapy are expected, which is usually the case in many institutions around the globe.